This project consists of several overlapping comprehensive, multidisciplinary population-based cohort and/or case-control studies to quantify the association between cancer-causing viruses (oncoviruses) with linked cancers. The studies focus on the role of the role of immunological alteration, infection and risk for cancer, including BL, NHL, Hodgkin lymphoma, kaposi sarcoma, lung cancer, cervical cancer, head and neck cancer, testicular cancer, breast cancer, penile cancer, and gastric cancer. Biological specimens (peripheral blood, saliva, tumor tissues), when available, are used to measure load of infectious agents, including HIV, HTLV-I/-II, HCV, and KSHV, also called HHV8, genetic variation in viral agents or the host to characterize association of biomarkers with cancer. Using the U.S. HIV/AIDS Cancer Match Study, among 567, 865 persons with HIV/AIDS, BL incidence showed two age-specific incidence peaks during the pediatric and adult/geriatric years and decreased with decreasing CD4 lymphocyte counts. The bimodal peaks for BL, in contrast to non-BL NHL, suggest effects of non-cumulative risk factors at different ages. In US registry-based cohort of 83,282 people with AIDS (1980-2006), overall mortality decreased from 302 deaths per 1000 person-years in 1980-1989, to 140 deaths per 1000 person-years in 1990-1995, and to 29 deaths per 1000 person-years in 1996-2006. AIDS-defining cancer related mortality decreased from 2.95 deaths per 1000 person-years in 1980-1989 to 0.65 deaths per 1000 person-years in 1996-2006, but the fraction of AIDS-defining cancer -related deaths increased from 1.05% to 2.47% in association with decreases in other AIDS-related deaths. NHL was the most common cancer-related cause of death (36% of deaths during 1996-2006) and lung cancer was the most common non-AIDS-defining cancer cause of death (21% of cancer-related deaths in 1996-2006). In US registry-based cohort of 83,282 people with AIDS (1980-2006), overall mortality decreased from 302 deaths per 1000 person-years in 1980-1989, to 140 deaths per 1000 person-years in 1990-1995, and to 29 deaths per 1000 person-years in 1996-2006. AIDS-defining cancer related mortality decreased from 2.95 deaths per 1000 person-years in 1980-1989 to 0.65 deaths per 1000 person-years in 1996-2006 , but the fraction of AIDS-defining cancer -related deaths increased from 1.05% to 2.47% in association with decreases in other AIDS-related deaths. NHL was the most common cancer-related cause of death (36% of deaths during 1996-2006) and lung cancer was the most common non-AIDS-defining cancer cause of death (21% of cancer-related deaths in 1996-2006). Using data from 263 254 adults and adolescents with AIDS (1980-2004) the U.S. HACM, we showed that risk was elevated for the 2 major AIDS-defining cancers: Kaposi sarcoma (SIRs, 5321 and 1347 in years 3-5 and 6-10, respectively) and non-Hodgkin lymphoma (SIRs, 32 and 15) and for all non-AIDS-defining cancers combined (SIRs, 1.7 and 1.6 in years 3-5 and 6-10, respectively) and for Hodgkin lymphoma and cancers of the oral cavity and/or pharynx, tongue, anus, liver, larynx, lung and/or bronchus, and penis. A four-year case-control study of classic (non-AIDS) Kaposi sarcoma and KSHV infection throughout the island of Sicily (where cKS and KSHV are endemic) was completed. Classic KS risk was significantly reduced with current smoking, and it was significantly and independently increased with diabetes and use of corticosteroids. Classic KS also was increased with residential exposure chromic luvisols, a soil associated with volcanoes. Merkel cell polyomavirus (MCPyV) was recently discovered in Merkel cell carcinoma (MCC), a clinically and pathologically heterogeneous malignancy of dermal neuroendocrine cells. We developed a tissue microarray (TMA) to characterize immunohistochemical staining of candidate tumor cell proteins and a quantitative PCR assay to detect MCPyV and measure viral loads. MCPyV was detected in 19 of 23 (74%) primary MCC tumors, but 8 of these had less than 1 viral copy per 300 cells. Viral abundance of 0.06-1.2 viral copies/cell was directly related to presence of retinoblastoma gene product (pRb) and terminal deoxyribonucleotidyl transferase (TdT) by immunohistochemical staining (p <or = 0.003). Higher viral abundance tumors tended to be associated with less p53 expression, younger age at diagnosis and longer survival (p <or = 0.08). Using data from the Multicenter AIDS Cohort Study (MACS), we showed that carriage of at least one copy of the T allele for the IL10 rs1800871 (as compared to no copies) was associated with decreased AIDS-NHL risk specific to lymphomas arising from the CNS (CC vs. CT/TT: OR = 0.3;95% CI 0.1, 0.7) but not systemically (CC vs. CT/TT: OR = 1.0;95% CI 0.5, 1.9) (Pheterogeneity = 0.03). Carriage of two copies of the 'low IL10'haplotype rs1800896_A/rs1800871_T/rs1800872_A was associated with decreased lymphoma risk that varied by number of copies (Ptrend = 0.02). Collaborations with private and academic laboratories were established to foster development of detection methods for known or possible cancer-associated viruses.